Pharmaceutical nanotechnologyProposal of stability categories for nano-dispersions obtained from pharmaceutical self-emulsifying formulations
Graphical abstract
Introduction
A considerable amount of research has been focused on lipid-based drug delivery systems (Porter et al., 2007). Among these different systems, the self-emulsifying formulations (SELFs) have been extensively investigated for managing poorly water-soluble drugs (Kuentz, 2012). When these formulations come into contact with water, fine dispersions are formed that typically promote the absorption of oral drugs. The composition of the preconcentrate defines the type of aqueous dispersion that is obtained. Both self-microemulsifying drug delivery systems (SMEDDS) and self-nanoemulsifying drug delivery systems (SNEDDS) have been used to describe preconcentrates that disperse in a colloidal size range (Müllertz et al., 2010, Jannin et al., 2008). Excellent reviews on lipid-based formulations have been written by, for example, Porter et al. (2008) and O’Driscoll and Griffin (2008). There are also reviews that focus on pharmaceutical microemulsions (Anton and Vandamme, 2011, Narang et al., 2007, Spernath and Aserin, 2006). The recent article by Anton and Vandamme (2011) is of particular interest as it questions whether many SMEDDS in the pharmaceutical field actually produce microemulsions upon dilution. Many of the so-called microemulsions may not be thermodynamically stable; therefore, they are essentially nano-emulsions. The most recent article by McClements (2012) also emphasizes the characteristics and differences of microemulsions and nano-emulsions.
There is certainly some confusion on differentiating between pharmaceutical microemulsions and nano-emulsions and consequently also between SMEDDS and SNEDDS. Stability data could differentiate between these systems, but such data are not available in most reports. In addition to the general uncertainty concerning the physical nature of the dispersions, the terminology of the systems is also not used consistently. Therefore, SNEDDS is used by many authors as an umbrella name for preconcentrates that result in either microemulsions or nano-emulsions. This usage may be acceptable if the terminology is clearly defined. Other scientists use SNEDDS with the assumption that the obtained dispersions are generally nano-emulsions. However, there is usually no rationale or experimental data provided to support such assumptions. Similarly, there is some confusion with usage of the terms SMEDDS and microemulsions.
The usage of the term microemulsion may not be optimal considering what we currently know about these systems, but it has been used for decades and it is well-established. The word microemulsion was previously coined in the pioneering days of the mid-20th century (Hoar and Schulman, 1943, Schulman and Riley, 1948, Schulman et al., 1959). A microemulsion is generally understood to be a thermodynamically stable fluid mixture of water, oil and surfactants (Stubenrauch, 2009). This definition differentiates microemulsions from nano-emulsions, which may only be kinetically stable. A differentiation between these systems can be troublesome because nano-emulsions are sometimes produced by low energy emulsification, such as through the dilution of self-emulsifying systems (Miyanoshita et al., 2011, Lopez-Montilla et al., 2002). Upon aqueous dilution, some preconcentrates have resulted in nano-emulsions with sizes that were less than 100 nm (Sole et al., 2012, Solans et al., 2005). This result makes differentiating between SNEDDS and SMEDDS complicated.
It might be argued that a microemulsion and any nano-emulsion are generally sufficiently stable for the absorption of oral drugs. Given the gastro-intestinal transit time, the drug absorption process is most likely similar in both systems. Constantinides et al. (1995) previously reported that the absorption of a fibrinogen receptor antagonist was independent of the droplet size in a diameter range from 10 to 1000 nm. However, such results are expected to be specific for the given drug and the investigated dosage. Furthermore, we only have limited knowledge concerning the robustness of preconcentrate dilution (Ditner et al., 2009) and how important it is for in vivo drug absorption. It appears that we cannot currently conclude that a differentiation between SMEDDS and SNEDDS is not of biopharmaceutical relevance.
There is another pharmaceutical application for which such differentiation is crucial. Diluted self-emulsifying formulations are, for example, used in preclinical studies of poorly water soluble drugs. This formulation technology is used in toxicological animal studies to reach a high drug exposure. These high concentrations are required for establishing adequate safety margins for the clinical development program. Among the different lipid-based formulations, the self-emulsifying systems are particularly attractive. A preconcentrate can be shipped to the study site, where the final dilution is prepared. There is typically a time delay between this dilution and the final administration of the dispersion; therefore, it is critical to have knowledge concerning the physical stability of the aqueous nano-dispersions.
Unfortunately, there is currently no stability classification of nano-dispersions. There is, however, a general categorization of lipid-based systems that was proposed by Pouton, 2000, Pouton, 2006. This lipid formulation classification system (LFCS) compares formulation types based on their composition and on their dispersion behavior. Therefore, simple oil formulations were assigned to category I, whereas mixtures of oil with a water-insoluble surfactant (HLB < 12) were classified as category II. Formulations of this category can include self-emulsifying drug delivery systems (SEDDS) that produce a dispersion droplet that is typically greater than 100 nm in size (Porter et al., 2008). In category III, the formulations contain a more hydrophilic surfactant or surfactant mixture (HLB > 12). The first subcategory IIIA still contains approximately 40–80% of triglycerides or mixed triglycerides as the oil component, whereas category IIIB was assigned to formulations that were only <20% oil. Moreover, IIIA formulations comprise approximately 0–40% hydrophilic co-solvents, whereas in IIIB, there is typically 20–50%. The typical particle size of the dispersion in category IIIA was reported to be approximately 100–250 nm, whereas the IIIB systems would yield droplets with diameters that are less than approximately 100 nm (Porter et al., 2008). There was even a category IV proposed for pure surfactant and co-solvent systems, in which a small particle size is generally obtained (<50 nm).
The LFCS is currently the most important classification system for lipid-based pharmaceutical formulations. This classification system is a helpful tool for defining a formulation strategy in drug development or later in the market. However, there is a further need to clarify self-emulsifying systems with respect to their dispersion stability. It is unclear which systems of category IIIB are SNEDDS or true SMEDDS. Moreover, some care is required when assigning a microemulsion to a system of type IV because the definition of a microemulsion requires the existence of an oil phase.
In summary, it is often unclear in pharmaceutical practice whether a micro- or nano-emulsion evolves upon dilution of a preconcentrate. Only a few stability studies of diluted self-emulsifying systems exist, but they are primarily outside of the pharmaceutical field (Sole et al., 2012). More stability data should be generated using pharmaceutical self-emulsifying systems. In addition to the need for experimental data, the analysis of pharmaceutical nano-dispersions could benefit from more recent theoretical developments (Gradzielski et al., 1996).
Thermodynamic arguments to describe the stability of microemlsions were previously used by Ruckenstein and Chi (1975). These arguments typically begin with the simplified approach of Eq. (1), which describes how the free energy of the dispersion, ΔGf, is obtained during microemulsification (Lawrence and Rees, 2000):where γ is the interfacial tension between the oil and water interface, ΔA represents the interfacial area difference and ΔS denotes the entropy change at a given temperature, T. Considering dispersions that consist of colloidal particles, it can be assumed that the change in area practically equals the interface of the generated spherical particles (number of N):
More critical is to make a meaningful assumption for the entropy term in Eq. (1). A very rough approximation is obtained from the product of the number of particles and the Boltzmann constant, kB. It is then possible to assume a limiting interfacial tension for which ΔGf goes to zero (Florence and Atwood, 2006):
This simple equation provides a first estimation for how the particle size is related to the limiting interfacial tension in a microemulsion. However, the entropy change, ΔS, requires a refined estimation for a more quantitative consideration. Colloidal-sized particle dispersion typically has high configurational entropy. This contribution to the entropy change during self-emulsification can be estimated using Eq. (4) by introducing the function f(ϕ):
Milner and Safran (1987) proposed the following equation for the entropy function f(ϕ):
Using this argument, a refined version of Eq. (3) is obtained:
An alternative theoretical approach to microemulsions is to consider the curvature energy of the surfactant films. The so-called Helfrich free energy, Fb, is described as a function of the spontaneous curvature c0, a bending constant (or Gaussian modulus) κ and the saddle splay modulus, (Helfrich, 1973, Gradzielski et al., 1996):where c1 and c2 hold for the principal curvatures of the surfactant film. Eq. (7) approximates the bending energy up to the second order in curvature and includes an integral over the entire surface A. For negative values of the Gaussian modulus, a discrete spherical structure is preferred, whereas positive values of this modulus favor saddle splay structures that can be, for example, found in bicontinuous microemulsions (Gradzielski et al., 1996). For a microemulsion of the O/W type, the favorable bending of the surfactant film naturally leads to an uptake of oil into the colloidal droplets. Some oil swelling is preferred, but there is a size limit Rm above which no more oil can be solubilized in the colloidal particles. The addition of more oil would lead to particles with an unfavorable curvature; therefore, at equilibrium, this excess oil is separated resulting in two phases. Knowledge about Rm helps to identify particles that are only kinetically stable because the excess solubilized oil leads to a larger particle radius. Unfortunately, the calculation of Rm is not straightforward. However, it is possible to relate the ratio of Rm and the spontaneous particle radius, R0 = 1/c1, to the mechanical moduli of a surfactant film (Gradzielski et al., 1996):Eq. (8) not only considers the bending energy of Eq. (7) but also the entropy contribution of Eq. (4). It makes sense to also consider the thermal fluctuations of colloidal particles such as droplets. Surfactant films and droplets are subject to harmonic deformations due to thermal energy (Witten and Pincus, 2010). A distribution of shape and size of the droplets consequently occurs. Therefore, the polydispersity naturally evolves as the result of thermal energy fluctuations. Based on such arguments, the following equation was proposed and successfully compared to the results from light scattering measurements (Gradzielski et al., 1996):Eq. (9) proposes a polydispersity, p, at the phase boundary that separates the two-phase system from a single phase of a stable dispersion, i.e., a microemulsion.
Gradzielski et al. (1996) used Eqs. (8), (9) together with an expression of the limiting interfacial tension, γL, to derive Eq. (10):Eq. (10) for this equilibrium consideration no longer contains the mechanical moduli. The result combines the polydispersity and maximal particle radius (at the phase boundary) and is therefore of theoretical and practical importance.
There is a need to investigate the physical stability of pharmaceutical dispersions obtained from various self-emulsifying systems. Moreover, theoretical arguments for how the particle size and polydispersity are related in microemulsions have, to the best of our knowledge, never been applied to pharmaceutical dispersions. This study first aims to propose stability categories for diluted nano-dispersions based on theoretical arguments (Gradzielski et al., 1996). Subsequently, a broad range of pharmaceutical preconcentrates are analyzed with respect to their aqueous dilution behavior. Following a thermal stress test, the dispersion stability is investigated using different physical methods, namely dynamic light scattering, ultrasound analysis and near-infrared (NIR) analytical centrifugation.
Section snippets
Materials
The surfactants Cremophor® RH40 (polyoxyl 40 hydrogenated castor oil), Cremophor® EL (polyoxyl 35 castor oil) and Solutol® HS15 (macrogol 15 hydroxystearate) as well as the viscosity enhancer Kollidon® 30 (povidone K-30, polyvinylpyrrolidone) were excipients from the company BASF AG (Ludwigshafen, Germany). The medium-chain triglycerides were received as Miglyol® 812 from the local vendor Hänseler AG (Herisau, Switzerland). The medium-chain partial glycerides Imwitor® 742 were purchased from
Proposed stability categories of diluted self-emulsifying formulations based on theoretical considerations
We considered two aqueous dilution levels of a preconcentrate with respect to pharmaceutical relevance, i.e., 1:10 and 1:100 (v/v). Eq. (6) is certainly a simplified model, but it provides a rough approximation of the limiting interfacial tension that has to be reached to obtain a system with thermodynamic stability. Fig. 1 displays the plots of the limiting interfacial tension as a function of the droplet diameter. A typical microemulsion would be expected to exhibit an interfacial tension of
Conclusions
Given the importance of self-emulsifying formulations, it is critical to understand the physical nature of the aqueous dispersions. To date, it appears that different research groups have used a nomenclature for the preconcentrates depending on what they expected to obtain during the dispersion. The different understandings and inconsistent use of the nomenclature among various research groups has been criticized by Anton and Vandamme (2011). It was important to take additional steps to provide
Acknowledgements
The stability experiments using ultrasonic resonator technology were part of a project that was funded by the Swiss Confederation's Innovation Promotion Agency (CTI). The authors would also like to thank the School of Life Sciences at the University of Applied Sciences and Arts (Muttenz, Switzerland) for their financial support.
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